SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study

SummaryBackgroundThe risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subsequent infection among seropositive young adults was studied prospectively.MethodsThe study population comprised 3,249 predominantly male, 18-20-year-old Marine recruits. Upon arrival at a Marine-supervised two-week quarantine, participants were assessed for baseline SARS-CoV-2 IgG seropositivity, defined as a 1:150 dilution or greater on receptor binding domain and full-length spike protein enzyme-linked immunosorbent (ELISA) assays. SARS-CoV-2 infection was assessed by PCR at initiation, middle and end of the quarantine. After appropriate exclusions, including participants with a positive PCR during quarantine, we performed three biweekly PCR tests in both seropositive and in seronegative groups once recruits left quarantine and entered basic training and baseline neutralizing antibody titers on all subsequently infected seropositive and selected seropositive uninfected participants.FindingsAmong 189 seropositive participants, 19 (10.1%) had at least one positive PCR test for SARS-CoV-2 during the six-week follow-up (1.1 cases per person-year). In contrast, 1,079 (48.0%) of the 2,247 seronegative participants tested positive (6.2 cases per person-year). The incidence rate ratio was 0.18 (95% CI 0.11-0.28, p<0.00001). Among seropositive recruits, infection was associated with lower baseline full-length spike protein IgG titers (p<0.0001). Compared with seronegative recruits, seropositive recruits had about 10-fold lower viral loads (ORF1ab gene, p<0.005), and trended towards shorter duration of PCR positivity (p=0.18) and more frequent asymptomatic infections (p=0.13). Among seropositive participants, baseline neutralizing titers were detected in 45 of 54 (83.3%) uninfected and in 6 of 19 (31.6%) infected participants during the 6 weeks of observation (ID50 difference p<.0001).InterpretationSeropositive young adults had about one-fifth the risk of subsequent infection compared with seronegative individuals. Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralization activity or immunity against subsequent infection. These findings may be relevant for optimization of mass vaccination strategies.FundingDefense Health Agency and Defense Advanced Research Projects Agency

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Titers of Neutralizing Antibodies against SARS-CoV-2 Are Independent of Symptoms of Non-Severe COVID-19 in Young Adults

Viruses ◽

10.3390/v13020284 ◽

2021 ◽

Vol 13 (2) ◽

pp. 284

Author(s):

Hulda R. Jonsdottir ◽

Michel Bielecki ◽

Denise Siegrist ◽

Thomas W. Buehrer ◽

Roland Züst ◽

...

Keyword(s):

Young Adults ◽

Neutralizing Antibodies ◽

Severe Disease ◽

Humoral Response ◽

Neutralizing Antibody ◽

Neutralization Assay ◽

Asymptomatic Infection ◽

Homogeneous Population ◽

Humoral Immune ◽

Antibody Titers

Neutralizing antibodies are an important part of the humoral immune response to SARS-CoV-2. It is currently unclear to what extent such antibodies are produced after non-severe disease or asymptomatic infection. We studied a cluster of SARS-CoV-2 infections among a homogeneous population of 332 predominantly male Swiss soldiers and determined the neutralizing antibody response with a serum neutralization assay using a recombinant SARS-CoV-2-GFP. All patients with non-severe COVID-19 showed a swift humoral response within two weeks after the onset of symptoms, which remained stable for the duration of the study. One month after the outbreak, titers in COVID-19 convalescents did not differ from the titers of asymptomatically infected individuals. Furthermore, symptoms of COVID-19 did not correlate with neutralizing antibody titers. Therefore, we conclude that asymptomatic infection can induce the same humoral immunity as non-severe COVID-19 in young adults.

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Immune responses to SARS-CoV-2 infection in hospitalized pediatric and adult patients

Science Translational Medicine ◽

10.1126/scitranslmed.abd5487 ◽

2020 ◽

Vol 12 (564) ◽

pp. eabd5487 ◽

Cited By ~ 20

Author(s):

Carl A. Pierce ◽

Paula Preston-Hurlburt ◽

Yile Dai ◽

Clare Burn Aschner ◽

Natalia Cheshenko ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Pediatric Patients ◽

Neutralizing Antibody ◽

Children And Youth ◽

Spike Protein ◽

Serum Concentrations ◽

Antiviral Immune Response ◽

Antibody Titers ◽

Ifn Γ

Children and youth infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have milder disease than do adults, and even among those with the recently described multisystem inflammatory syndrome, mortality is rare. The reasons for the differences in clinical manifestations are unknown but suggest that age-dependent factors may modulate the antiviral immune response. We compared cytokine, humoral, and cellular immune responses in pediatric (children and youth, age <24 years) (n = 65) and adult (n = 60) patients with coronavirus disease 2019 (COVID-19) at a metropolitan hospital system in New York City. The pediatric patients had a shorter length of stay, decreased requirement for mechanical ventilation, and lower mortality compared to adults. The serum concentrations of interleukin-17A (IL-17A) and interferon-γ (IFN-γ), but not tumor necrosis factor–α (TNF-α) or IL-6, were inversely related to age. Adults mounted a more robust T cell response to the viral spike protein compared to pediatric patients as evidenced by increased expression of CD25+ on CD4+ T cells and the frequency of IFN-γ+ CD4+ T cells. Moreover, serum neutralizing antibody titers and antibody-dependent cellular phagocytosis were higher in adults compared to pediatric patients with COVID-19. The neutralizing antibody titer correlated positively with age and negatively with IL-17A and IFN-γ serum concentrations. There were no differences in anti-spike protein antibody titers to other human coronaviruses. Together, these findings demonstrate that the poor outcome in hospitalized adults with COVID-19 compared to children may not be attributable to a failure to generate adaptive immune responses.

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Severe Acute Respiratory Syndrome-Associated Coronavirus Vaccines Formulated with Delta Inulin Adjuvants Provide Enhanced Protection while Ameliorating Lung Eosinophilic Immunopathology

Journal of Virology ◽

10.1128/jvi.02980-14 ◽

2014 ◽

Vol 89 (6) ◽

pp. 2995-3007 ◽

Cited By ~ 79

Author(s):

Yoshikazu Honda-Okubo ◽

Dale Barnard ◽

Chun Hao Ong ◽

Bi-Hung Peng ◽

Chien-Te Kent Tseng ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Neutralizing Antibodies ◽

Case Fatality ◽

Neutralizing Antibody ◽

The Elderly ◽

Spike Protein ◽

Interleukin 4 ◽

Unique Problem ◽

Antibody Titers ◽

Ifn Γ

ABSTRACTAlthough the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) epidemic was controlled by nonvaccine measures, coronaviruses remain a major threat to human health. The design of optimal coronavirus vaccines therefore remains a priority. Such vaccines present major challenges: coronavirus immunity often wanes rapidly, individuals needing to be protected include the elderly, and vaccines may exacerbate rather than prevent coronavirus lung immunopathology. To address these issues, we compared in a murine model a range of recombinant spike protein or inactivated whole-virus vaccine candidates alone or adjuvanted with either alum, CpG, or Advax, a new delta inulin-based polysaccharide adjuvant. While all vaccines protected against lethal infection, addition of adjuvant significantly increased serum neutralizing-antibody titers and reduced lung virus titers on day 3 postchallenge. Whereas unadjuvanted or alum-formulated vaccines were associated with significantly increased lung eosinophilic immunopathology on day 6 postchallenge, this was not seen in mice immunized with vaccines formulated with delta inulin adjuvant. Protection against eosinophilic immunopathology by vaccines containing delta inulin adjuvants correlated better with enhanced T-cell gamma interferon (IFN-γ) recall responses rather than reduced interleukin-4 (IL-4) responses, suggesting that immunopathology predominantly reflects an inadequate vaccine-induced Th1 response. This study highlights the critical importance for development of effective and safe coronavirus vaccines of selection of adjuvants based on the ability to induce durable IFN-γ responses.IMPORTANCECoronaviruses such as SARS-CoV and Middle East respiratory syndrome-associated coronavirus (MERS-CoV) cause high case fatality rates and remain major human public health threats, creating a need for effective vaccines. While coronavirus antigens that induce protective neutralizing antibodies have been identified, coronavirus vaccines present a unique problem in that immunized individuals when infected by virus can develop lung eosinophilic pathology, a problem that is further exacerbated by the formulation of SARS-CoV vaccines with alum adjuvants. This study shows that formulation of SARS-CoV spike protein or inactivated whole-virus vaccines with novel delta inulin-based polysaccharide adjuvants enhances neutralizing-antibody titers and protection against clinical disease but at the same time also protects against development of lung eosinophilic immunopathology. It also shows that immunity achieved with delta inulin adjuvants is long-lived, thereby overcoming the natural tendency for rapidly waning coronavirus immunity. Thus, delta inulin adjuvants may offer a unique ability to develop safer and more effective coronavirus vaccines.

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Modified Vaccinia Ankara Based SARS-CoV-2 Vaccine Expressing Full-Length Spike Induces Strong Neutralizing Antibody Response

10.1101/2020.06.27.175166 ◽

2020 ◽

Cited By ~ 1

Author(s):

Nanda Kishore Routhu ◽

Sailaja Gangadhara ◽

Narayanaiah Cheedarla ◽

Ayalnesh Shiferaw ◽

Sheikh Abdul Rahman ◽

...

Keyword(s):

Antibody Response ◽

Room Temperature ◽

Vaccine Candidate ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Full Length ◽

Spike Protein ◽

Strongly Correlated ◽

Igg Antibodies ◽

Potential Vaccine

AbstractThere is a great need for the development of vaccines for preventing SARS-CoV-2 infection and mitigating the COVID-19 pandemic. Here, we developed two modified vaccinia Ankara (MVA) based vaccines which express either a membrane anchored full-length spike protein (MVA/S) stabilized in a prefusion state or the S1 region of the spike (MVA/S1) which forms trimers and is secreted. Both immunogens contained the receptor-binding domain (RBD) which is a known target of antibody-mediated neutralization. Following immunizations with MVA/S or MVA/S1, both spike protein recombinants induced strong IgG antibodies to purified full-length SARS-CoV-2 spike protein. The MVA/S induced a robust antibody response to purified RBD, S1 and S2 whereas MVA/S1 induced an antibody response to the S1 region outside of the RBD region. Both vaccines induced an antibody response in the lung and that was associated with induction of bronchus-associated lymphoid tissue. MVA/S but not MVA/S1 vaccinated mice generated robust neutralizing antibody responses against SARS-CoV-2 that strongly correlated with RBD antibody binding titers. Mechanistically, S1 binding to ACE-2 was strong but reduced following prolonged pre-incubation at room temperature suggesting confirmation changes in RBD with time. These results demonstrate MVA/S is a potential vaccine candidate against SARS-CoV-2 infection.

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Reduced binding and neutralization of infection- and vaccine-induced antibodies to the B.1.351 (South African) SARS-CoV-2 variant

10.1101/2021.02.20.432046 ◽

2021 ◽

Cited By ~ 4

Author(s):

Venkata Viswanadh Edara ◽

Carson Norwood ◽

Katharine Floyd ◽

Lilin Lai ◽

Meredith E. Davis-Gardner ◽

...

Keyword(s):

South African ◽

Receptor Binding ◽

Symptom Onset ◽

Protective Immunity ◽

Neutralizing Antibody ◽

Spike Protein ◽

Receptor Binding Domain ◽

Live Virus ◽

Fold Reduction ◽

Antibody Titers

SUMMARYThe emergence of SARS-CoV-2 variants with mutations in the spike protein is raising concerns about the efficacy of infection- or vaccine-induced antibodies to neutralize these variants. We compared antibody binding and live virus neutralization of sera from naturally infected and spike mRNA vaccinated individuals against a circulating SARS-CoV-2 B.1 variant and the emerging B.1.351 variant. In acutely-infected (5-19 days post-symptom onset), convalescent COVID-19 individuals (through 8 months post-symptom onset) and mRNA-1273 vaccinated individuals (day 14 post-second dose), we observed an average 4.3-fold reduction in antibody titers to the B.1.351-derived receptor binding domain of the spike protein and an average 3.5-fold reduction in neutralizing antibody titers to the SARS-CoV-2 B.1.351 variant as compared to the B.1 variant (spike D614G). However, most acute and convalescent sera from infected and all vaccinated individuals neutralize the SARS-CoV-2 B.1.351 variant, suggesting that protective immunity is retained against COVID-19.

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Full-Length Computational Model of the SARS-CoV-2 Spike Protein and Its Implications for a Viral Membrane Fusion Mechanism

Viruses ◽

10.3390/v13061126 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1126

Author(s):

Wataru Nishima ◽

Marta Kulik

Keyword(s):

Membrane Fusion ◽

Neutralizing Antibody ◽

Infection Process ◽

Proteolytic Processing ◽

Full Length ◽

Spike Protein ◽

Fusion Model ◽

Protein Uptake ◽

Host Membrane ◽

Short Time

The SARS-CoV-2 virus has now become one of the greatest causes of infectious death and morbidity since the 1918 flu pandemic. Substantial and unprecedented progress has been made in the elucidation of the viral infection process in a short time; however, our understanding of the structure–function dynamics of the spike protein during the membrane fusion process and viral uptake remains incomplete. Employing computational approaches, we use full-length structural models of the SARS-CoV-2 spike protein integrating Cryo-EM images and biophysical properties, which fill the gaps in our understanding. We propose a membrane fusion model incorporating structural transitions associated with the proteolytic processing of the spike protein, which initiates and regulates a series of events to facilitate membrane fusion and viral genome uptake. The membrane fusion mechanism highlights the notable role of the S1 subunit and eventual mature spike protein uptake through the host membrane. Our comprehensive view accounts for distinct neutralizing antibody binding effects targeting the spike protein and the enhanced infectivity of the SARS-CoV-2 variant.

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Seroprevalence of SARS-CoV-2 IgG antibodies, in Corsica (France), April and June 2020.

10.1101/2020.09.29.20201368 ◽

2020 ◽

Cited By ~ 1

Author(s):

Lisandru Capai ◽

Nazli Ayhan ◽

Shirley Masse ◽

Jean Canarelli ◽

Stephane Priet ◽

...

Keyword(s):

Neutralization Test ◽

Age Groups ◽

Neutralizing Antibody ◽

Blood Analysis ◽

Spike Protein ◽

P Value ◽

Igg Antibodies ◽

Antibody Titers ◽

The Impact ◽

Sera Samples

Our aim was to assess the seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection after the lockdown in a sample of the Corsican population. Between 16th April and 15th June 2020, 2,312 residual sera were collected from patients having carried out a blood analysis in one of the participating laboratories. Residual sera obtained from persons of all ages were tested for the presence of anti-SARS-CoV-2 IgG using the EUROIMMUN enzyme immunoassay kit for semiquantitative detection of IgG antibodies against S1 domain of viral spike protein (ELISA-S). Borderline and positive samples in ELISA-S were also tested with an in-house virus neutralization test (VNT). Prevalence values were adjusted for sex and age. A total of 1,973 residual sera samples were included in the study. The overall seroprevalence based on ELISA-S was 5.27% [95% confidence interval (CI) 4.33-6.35] and 5.46% [4.51-6.57] after adjustment. Gender was not associated with IgG detection. However, significant differences were observed between age groups (p-value = 1 E-5) and particularly for people being younger than 50 years of age (Odd ratio (OR) = 2.86 95% CI [1.80- 4.53]; p-value <0.000001*). The prevalence of neutralizing antibody titers ≥40 was of 3% [2.28-3.84]. In conclusion the present study showed that a low seroprevalence for COVID-19 in Corsica in accordance with values reported for other French regions in which the impact of the pandemic was low.

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Long-term SARS-CoV-2 RNA Shedding and its Temporal Association to IgG Seropositivity

10.1101/2020.06.02.20120774 ◽

2020 ◽

Cited By ~ 3

Author(s):

Vineet Agarwal ◽

AJ Venkatakrishnan ◽

Arjun Puranik ◽

Christian Kirkup ◽

Agustin Lopez-Marquez ◽

...

Keyword(s):

Upper Bound ◽

Neutralizing Antibody ◽

Initial Diagnosis ◽

Viral Rna ◽

Temporal Association ◽

Viral Loads ◽

Antibody Titers ◽

The Mean

Analysis of 851 COVID-19 patients with a SARS-CoV-2-positive PCR at follow-up shows 99 patients remained SARS-CoV-2-positive after four weeks from initial diagnosis. Surprisingly, a majority of these long-term viral RNA shedders were not hospitalized (61 of 99), with variable PCR Crossing point values over the month post diagnosis. For the 851-patient cohort, the mean lower bound of viral RNA shedding was 17.3 days (SD: 7.8), and the mean upper bound of viral RNA shedding from 668 patients transitioning to confirmed PCR-negative status was 22.7 days (SD: 11.8). Among 104 patients with an IgG test result, 90 patients were seropositive to date, with mean upper bound of time to seropositivity from initial diagnosis being 37.8 days (95%CI: 34.3-41.3). Juxtaposing IgG/PCR tests revealed that 14 of 90 patients are non-hospitalized and seropositive yet shed viral RNA. This study emphasizes the need for monitoring viral loads and neutralizing antibody titers in long-term shedders.

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Immunogenicity of Bacillus anthracis Protective Antigen Domains and Efficacy of Elicited Antibody Responses Depend on Host Genetic Background

Clinical and Vaccine Immunology ◽

10.1128/cvi.00015-08 ◽

2008 ◽

Vol 15 (7) ◽

pp. 1115-1123 ◽

Cited By ~ 32

Author(s):

Nareen Abboud ◽

Arturo Casadevall

Keyword(s):

Bacillus Anthracis ◽

Antibody Titer ◽

Genetic Background ◽

Protective Antigen ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Full Length ◽

Mouse Strains ◽

Neutralizing Capacity ◽

Antibody Titers

ABSTRACT Neutralizing antibodies to Bacillus anthracis protective antigen (PA), a component of anthrax toxin, mediate protection against anthrax. PA is antigenically complex and can elicit protective and nonprotective antibodies. Furthermore, vaccinated individuals demonstrate considerable variability in their antibody responses to PA. To explore the relationship between PA structure and antigenicity, we produced Escherichia coli strains expressing full-length PA (PA1-4), domains 2 to 4 (PA2-4), domain 1, (PA1), and domain 4 (PA4) and evaluated the immunogenicities and protective efficacies of the protein fractions in four mouse strains (strains A/J, BALB/c, C57BL/6, and Swiss Webster). Immunization with PA1-4 resulted in significantly higher lethal toxin-neutralizing antibody titers than immunization with any recombinant protein (rPA) fraction of PA. The magnitude and neutralizing capacity of the antibody response to full-length PA and its fragments varied depending on the mouse strain. We found no correlation between the antibody titer and the neutralizing antibody titer for A/J and Swiss Webster mice. In C57BL/6 mice, antibody titers and neutralization capacity correlated for two of four rPA domain proteins tested, while BALB/c mice displayed a similar correlation with only one rPA. By correlating the reactivity of immune sera with solvent-exposed linear peptide segments of PA, we tentatively assign the presence of four new linear B-cell epitopes in PA amino acids 121 to 150, 143 to 158, 339 to 359, and 421 to 440. We conclude that the genetic background of the host determines the relative efficacy of the antitoxin response. The results suggest that the variability observed in vaccination studies with PA-derived vaccines is a result of host heterogeneity and implies a need to develop other antigens as vaccine candidates.

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